Glycinergic transmission

Kirsch, Joachim

doi:10.1007/s00441-006-0261-x

Cited by 62 publications

(43 citation statements)

References 53 publications

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“…4 A and C) and spinal cord (Fig. 4 B and C), where glycinergic neurotransmission is prominent (20,21). In these regions, the vast majority of NL4 immunoreactive puncta were associated with GlyR-positive clusters and not with PSD-95 (Fig.…”

Section: Nl4 Is Present At Inhibitory Synapses Throughout the Cnsmentioning

confidence: 99%

Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina

Hoon

Soykan

Falkenburger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

193

197

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Neuroligins (NL1-NL4) are postsynaptic adhesion proteins that control the maturation and function of synapses in the central nervous system (CNS). Loss-of-function mutations in NL4 are linked to rare forms of monogenic heritable autism, but its localization and function are unknown. Using the retina as a model system, we show that NL4 is preferentially localized to glycinergic postsynapses and that the loss of NL4 is accompanied by a reduced number of glycine receptors mediating fast glycinergic transmission. Accordingly, NL4-deficient ganglion cells exhibit slower glycinergic miniature postsynaptic currents and subtle alterations in their stimuluscoding efficacy, and inhibition within the NL4-deficient retinal network is altered as assessed by electroretinogram recordings. These data indicate that NL4 shapes network activity and information processing in the retina by modulating glycinergic inhibition. Importantly, NL4 is also targeted to inhibitory synapses in other areas of the CNS, such as the thalamus, colliculi, brainstem, and spinal cord, and forms complexes with the inhibitory postsynapse proteins gephyrin and collybistin in vivo, indicating that NL4 is an important component of glycinergic postsynapses.synaptogenesis | inhibitory transmission | visual processing I n rodents, postsynaptic adhesion proteins of the neuroligin family (NL1-NL4) are expressed throughout the central nervous system (CNS) (1-3) and essential for synapse organization and function (2-5). In vivo, each NL isoform localizes to specific synapse subpopulations, with NL1, NL2, and NL3 predominantly associating with glutamatergic, GABAergic, or both types of postsynapses, respectively (1, 6-9).Thus far, the distribution and function of the fourth NL isoform has remained unclear, despite the wide interest triggered by the causal link of specific loss-of-function mutations in NL4 to cases of autism, which led to the notion that aberrant synaptic transmission may cause autism spectrum disorders (ASDs) (10).We examined the distribution of NL4 in the mouse retina, a well-characterized region of the CNS with distinct, topographically organized glutamatergic, GABAergic, and glycinergic synapses, which has recently allowed us to characterize crucial aspects of NL2 distribution and function (8). Additionally, we assessed NL4 function by studying synaptic activity and visual processing in the NL4-deficient (NL4-KO; ref.3) mouse retina. Finally, we studied NL4 localization in the rest of the CNS and identified some of its key binding partners at the synapse. Results NL4 Is Localized to Glycinergic Postsynapses in the Retina.We characterized the distribution of NL4 by immunohistochemistry by using an isoform-specific antibody (3) (Fig. 1). A punctate labeling was detected in the inner plexiform layer (IPL) of wildtype (WT) but not NL4-KO retinae (Fig. 1A). NL4-positive puncta were abundant in the outer IPL but sparse in the rest of the IPL (Fig. 1A), which is reminiscent of glycine receptor (GlyR) distribution in the retina (11,12). Indeed, upon co...

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Section: Nl4 Is Present At Inhibitory Synapses Throughout the Cnsmentioning

confidence: 99%

Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina

Hoon

Soykan

Falkenburger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

193

197

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“…synapses [71]. Typical excitatory transmitters of the mammalian CNS are glutamate [65] or dopamine whereas gamma-amniobutyric (GABA) and glycine are inhibitory transmitters [94]. Glutamate is also the typical transmitter between the upper and lower motoneurons.…”

Section: Sonic Hedgehog Signalingmentioning

confidence: 99%

Developmental and Functional Nature of Human iPSC Derived Motoneurons

Stockmann

Linta

Föhr

et al. 2011

Stem Cell Rev and Rep

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“…␥-Aminobutyric acid (GABA) 2 and glycine are the predominant inhibitory neurotransmitters in the central nervous system and also maintain important functions in several peripheral tissues (1)(2)(3)(4)(5). The ionotropic GABA A and glycine receptors (GABA A Rs and GlyRs) belong to the Cys-loop receptor superfamily, which also comprises nicotinic acetylcholine receptors (nAChRs) and 5-HT 3 receptors (5-HT 3 Rs) (3)(4)(5)(6)(7)(8)(9).…”

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confidence: 99%

“…The receptors mediate a wide array of important physiological functions and are validated drug targets in the treatment of numerous disorders (10 -14). The GlyRs in the spinal cord and brain stem are of key importance for motor functions and sensory signaling in vision and audition (1,5,15). The GlyRs are formed from the ␣1-␣4 and ␤ subunits, and both homomeric ␣ and heteromeric ␣␤ subtypes exist (1,5,15).…”

mentioning

confidence: 99%

“…The GlyRs in the spinal cord and brain stem are of key importance for motor functions and sensory signaling in vision and audition (1,5,15). The GlyRs are formed from the ␣1-␣4 and ␤ subunits, and both homomeric ␣ and heteromeric ␣␤ subtypes exist (1,5,15). To be able to elucidate the composition of the native GABA A R and GlyR populations and delineate the physiological roles governed by specific receptor subtypes, there is a profound need for identification and development of selective ligands targeting one or a subset of subtypes.…”

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confidence: 99%

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Ginkgolide X Is a Potent Antagonist of Anionic Cys-loop Receptors with a Unique Selectivity Profile at Glycine Receptors

Jensen

Bergmann

Sander

et al. 2010

Journal of Biological Chemistry

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The novel ginkgolide analog ginkgolide X was characterized functionally at human glycine and ␥-aminobutyric acid type A receptors (GlyRs and GABA A Rs, respectively) in the fluorescence-based FLIPR TM Membrane Potential assay. The compound inhibited the signaling of all GABA A R subtypes included in the study with high nanomolar/low micromolar IC 50 values, except the 1 receptor at which it was a significantly weaker antagonist. Ginkgolide X also displayed high nanomolar/low micromolar IC 50 values at the homomeric ␣1 and ␣2 GlyRs, whereas it was inactive at the heteromeric ␣1␤ and ␣2␤ subtypes at concentrations up to 300 M. Thus, the functional properties of the compound were significantly different from those of the naturally occurring ginkgolides A, B, C, J, and M but similar to those of picrotoxin. In a mutagenesis study the 6 M2 residues in the GlyR ion channel were identified as the primary molecular determinant of the selectivity profile of ginkgolide X, and a 6 M2 ring consisting of five Thr residues was found to be of key importance for its activity at the GABA A R. Conformational analysis and docking of low-energy conformations of the native ginkgolide A and ginkgolide X into a ␣1 GlyR homology model revealed two distinct putative binding sites formed by the 6 M2 residues together with the 2 residues and the 10 and 13 residues, respectively. Thus, we propose that the distinct functionalities of ginkgolide X compared with the other ginkgolides could arise from different flexibility and thus different binding modes to the ion channel of the anionic Cys-loop receptor. ␥-Aminobutyric acid (GABA)2 and glycine are the predominant inhibitory neurotransmitters in the central nervous system and also maintain important functions in several peripheral tissues (1-5). The ionotropic GABA A and glycine receptors (GABA A Rs and GlyRs) belong to the Cys-loop receptor superfamily, which also comprises nicotinic acetylcholine receptors (nAChRs) and 5-HT 3 receptors (5-HT 3 Rs) (3-9). The Cys-loop receptors are homomeric or heteromeric assemblies of five subunits, and the pentameric receptor complex consists of three domains: an extracellular domain composed of the N-terminal domains of the five subunits, a transmembrane domain formed by the M1-M4 ␣-helices of the five subunits (including an ion channel predominantly formed by the five M2 helices), and an intracellular domain composed primarily of the large second intracellular loops of the five subunits (4, 7). Signal transduction through the Cys-loop receptor is initiated by binding of the agonist to orthosteric sites situated at the interfaces between the N-terminal domains of the subunits, and this elicits a conformation change in the pentameric complex leading to flux of ions through the ion channel. Whereas nAChRs and 5-HT 3

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Glycinergic transmission

Cited by 62 publications

References 53 publications

Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina

Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina

Developmental and Functional Nature of Human iPSC Derived Motoneurons

Ginkgolide X Is a Potent Antagonist of Anionic Cys-loop Receptors with a Unique Selectivity Profile at Glycine Receptors

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